1. Field of the Invention
This invention relates to a new class of steroidal anti-inflammatory compounds. More specifically, it relates to certain 17-esters, a 17,21-diester and 17,21-orthoesters of cloprednol, (6-chloro-11.beta.,17.alpha.,21-trihydroxypregna-1,4,6-triene-3,20-dione), and their use as topical anti-inflammatories.
2. Prior Art
Cloprednol and its 21-esters are known compounds as set forth in U.S. Pat. No. 3,232,965 to Ringold and Rosenkranz. The compound and its 21-esters are generally given orally to aid in reducing the pain of arthritis and other inflammatory conditions. It is generally known that certain 17-esters of pregnadienes can be prepared by forming the 17,21-orthoester of the 17,21-diol and hydrolyzing the orthoester to obtain a 17-acetate. See for example, French Pat. No. 1,469,675; U.S. Pat. No. 3,980,778; and German Patent Application DT No. 2,055,221.
It has been suggested in a Report dated Dec. 15, 1975 published by Kidder, Peabody and Co. entitled "The Drug Industry--Hormones: Topical Corticosteroids" that cloprednol might be applied topically and may promise a short-acting steroid molecule that might offer toxicity advantages over older steroids. Unfortunately, cloprednol itself exhibites limited topical, anti-inflammatory activities. Although the 21-esters of cloprednol exhibit slightly greater topical anti-inflammatory activity (as estimated by a vasoconstriction assay) than cloprednol and appear to have short half-lives, as does cloprednol, they exhibit substantial systemic activity as measured in small animal assays. It is desirable, of course, to use topical corticosteroids which have a favorable therapeutic ratio of anti-inflammatory systemic activity, i.e. the higher the value of the ratio, the better the compound, assuming the topical activity is in the correct range. Surprisingly, we have now discovered that certain 17-esters, a 17,21-diester and certain 17,21-orthoesters of cloprednol exhibit a more favorable therapeutic ratio of anti-inflammatory (i.e. vasoconstriction) to systemic activity than cloprednol itself or the corresponding 21-esters and that the compounds of this invention are also unexpectedly superior to the heretofore unknown 17-acetate of cloprednol.